Oxidative Stress, Testosterone, and Cognition among Caucasian and Mexican-American Men with and without Alzheimer's Disease

Abstract

Background The use of testosterone among aging men has been increasing, but results from studies addressing the effectiveness of testosterone replacement therapy (TRT) have been equivocal. Objective Given our prior pre-clinical studies that reported a major influence of oxidative stress (OS) on testosterone’s neuroprotective effects, we investigated whether the negative effects of testosterone on brain function were predicted by oxidative load. Methods In order to test our hypothesis, we determined whether circulating total testosterone and luteinizing hormone (LH) correlated with cognition in a subset of the Texas Alzheimer’s Research & Care Consortium (TARCC) cohort, consisting of Caucasian (n=116) and Mexican-American (n=117) men. We also assessed whether OS (as indexed by homocysteine levels) modified this relationship between sex hormones and cognition, and whether the levels of two antioxidants, superoxide dismutase-1 (SOD), and glutathione S-transferase (GST) varied as a function of circulating testosterone. Results In a low OS environment, testosterone was positively associated with the level of the antioxidant, GST, while no deleterious effects on cognitive function were noted. In contrast, under conditions of high OS (homocysteine levels >12 μM), testosterone and LH were associated with cognitive impairment, but only among Caucasians. The ethnic difference was attributed to significantly higher GST levels among Mexican-Americans. Conclusion While testosterone may be beneficial under conditions of low OS, testosterone appears to have negative consequences under conditions of elevated OS, but only in Caucasians. Mexican-Americans, however, were protected from any deleterious effects of testosterone, potentially due to higher levels of endogenous antioxidant defenses such as GST.

Alzheimer, mitochondria and gender

“…The levels of circulating testosterone, the main male sex hormone, present a gradual reduction over the life course, decreasing of approximately 2% every year after the age of 30 years (Feldman et al 2002), while brain oxidative stress shows a gradual increase with age in men (Peskind et al 2014). Moreover, circulating levels of testosterone were positively correlated with the level of the antioxidant glutathione S-transferase in a low oxidative stress environment in Caucasian and Mexican-American men (over 60 years old) (Cunningham et al 2014), while in gonadectomized (GDX) rats, SOD and GSH activity significantly decreased in the hippocampus when compared to that of sham-operated animals (Meydan et al 2010). Again, these effects were prevented in animals after testosterone administration.…”

A model for the induction of autism in the ecosystem of the human body: the anatomy of a modern pandemic?

“…3 . For example, the gender bias associated with autism is understandable given the observations that testosterone ‘depresses resistance to oxidative stress’ in an animal model ( 52 ) and may be deleterious for brain function under conditions of high oxidative stress in humans ( 53 ). Further, the association between autism and use of the drug valproic acid ( 54 ), which causes microglia activation in cultured glial cells ( 55 ), is also consistent with the view presented in Fig.…”

Neuroprotective and neurotoxic outcomes of androgens and estrogens in an oxidative stress environment

“…Further, the presence of 70 kDa androgen receptor fragment increases with age [80]. Interestingly, aging is associated with increased oxidative stress [81,82]. Thus, it is a possible oxidative stress may play a role in androgen receptor degradation, as oxidative stress has a bidirectional relationship with calcium-dependent calpain proteases [83][84][85] that can cleave full-length androgen receptors into 70 kDa fragments [86][87][88][89].…”